Zirconium

Summary The action of Zirconium (Zr) on biological systems presents an enigma. It is ubiquitous, being present in nature in amounts higher than most trace elements. It is taken up by plants from soil and water and accumulated in certain tissues. The entry into animal systems in vivo is related to the mode of exposure and the concentration in the surrounding environment. Retention is initially in soft tissues and then slowly in the bone. The metal is able to cross the blood brain-barrier and is deposited in the brain and the placental barrier to enter milk. The daily human uptake has been known to be as high as 125 mg. The level of toxicity has been found to be moderately low, both in histological and cytological studies. The toxic effects induced by very high concentrations are nonspecific in nature. Despite the presence and retention in relatively high quantities in biological systems, Zr has not yet been associated with any specific metabolic function. Very little information is available about its interaction with the compounds of the genetical systems, such as nucleic acids. Apparently, the metal is neither an essential nor toxic element in the conventional sense. However, the increasing exposure to this element through its increasing use in new materials and following radioactive fallout, has increased the importance of the study of its effects on living organisms. The tetravalent nature of the ionic state and the high stability of the compounds formed are important factors that need to be considered, as also the accumulation of this element in the brain, reminiscent of the relationship between Al³⁺ and Alzheimer's disease.     

HUMAN NATURE AND ENHANCEMENT

Appeals to the idea of human nature are frequent in the voluminous literature on the ethics of enhancing human beings through biotechnology. Two chief concerns about the impact of enhancements on human nature have been voiced. The first is that enhancement may alter or destroy human nature. The second is that if enhancement alters or destroys human nature, this will undercut our ability to ascertain the good because, for us, the good is determined by our nature. The first concern assumes that altering or destroying human nature is in itself a bad thing. The second concern assumes that human nature provides a standard without which we cannot make coherent, defensible judgments about what is good.
I will argue (1) that there is nothing wrong, per se, with altering or destroying human nature, because, on a plausible understanding of what human nature is, it contains bad as well as good characteristics and there is no reason to believe that eliminating some of the bad would so imperil the good as to make the elimination of the bad impermissible, and (2) that altering or destroying human nature need not result in the loss of our ability to make judgments about the good, because we possess a conception of the good by which we can and do evaluate human nature. I will argue that appeals to human nature tend to obscure rather than illuminate the debate over the ethics of enhancement and can be eliminated in favor of more cogent considerations.     

Hydrogen exchange in a large 29 kD protein and characterization of molten globule aggregation by NMR

The nature of denatured ensembles of the enzyme human carbonic anhydrase (HCA) has been extensively studied by various methods in the past. The protein constitutes an interesting model for folding studies that does not unfold by a simple two-state transition, instead a molten globule intermediate is highly populated at 1.5 M GuHCl. In this work, NMR and H/D exchange studies have been conducted on one of the isozymes, HCA I. The H/D exchange studies, which were enabled by the previously obtained resonance assignment of HCA I, have been used to identify unfolded forms that are accessible from the native state. In addition, the GuHCl-induced unfolded states of HCA I have also been characterized by NMR at GuHCl concentrations in the 0-5 M range. The most important findings in this work are as follows: (1) Amide protons located in the center of the beta-sheet require global unfolding events for efficient H/D exchange. (2) The molten globule and the native state give similar protection against H/D exchange for all of the observable amide protons (i.e., water seems not to efficiently penetrate the interior of the molten globule). (3) At high protein concentrations, the molten globule can form large aggregates, which are not detectable by solution-state NMR methods. (4) The unfolded state (U), present at GuHCl concentrations above 2 M, is composed of an ensemble of conformations having residual structures with different stabilities.     

The Terrace simultaneous chaining paradigm

Terrace and his colleagues (Chen et al., 1997) have developed a simultaneous chaining paradigm (SCP) that breaks new ground in the study of animal learning. It also suggests a sharp contrast with human serial learning, and is pertinent to the on-going (ever-lasting) disagreement about item-to-item vs. item-to-position associations. I shall review this work and suggest the outline of a possible TODAM-like memory model using position rather than context vectors that might eventually provide a theoretical underpinning for this important work of Terrace. However, so far all I have been able to show is that this model can learn but it has not yet been developed to the point where we can estimate parameter values and fit the SCP data.     

Characterization of the major regulatory element upstream of the human alpha-globin gene cluster.

The major positive regulatory activity of the human alpha-globin gene complex has been localized to an element associated with a strong erythroid-specific DNase I hypersensitive site (HS -40) located 40 kb upstream of the zeta 2-globin mRNA cap site. Footprint and gel shift analyses of the element have demonstrated the presence of four binding sites for the nuclear factor GATA-1 and two sites corresponding to the AP-1 consensus binding sequence. This region resembles one of the major elements of the beta-globin locus control region in its constitution and characteristics; this together with evidence from expression studies suggests that HS -40 is a primary element controlling alpha-globin gene expression.     

The complexity of living bodies and the structure of biological theories

It has been suggested that biological theories differ from physical theories because the subject matter of biology differs from the subject matter of physics especially in the fact that living bodies are more complex than nonliving bodies. It is shown that the interactional complexity of living bodies can only be expressed by invoking biological theories. The claim that living bodies are complex is, therefore, ultimately a claim about the nature of scientific theories rather than a claim about the nature of the subject matter of biology resting upon a presystematic judgement.     

Have we underestimated the importance of humans in the biogeography of free‐living terrestrial microorganisms?

The role of humans in the global dispersal of free‐living terrestrial microorganisms has received surprisingly little attention in the literature, compared with the frequent discussions of human dispersal for aquatic microbes. Here I argue that this area needs more study, using examples from the ecology of testate amoebae to illustrate the nature of the problem. The techniques of molecular ecology now make these ideas open to investigation in a way that would have been difficult in the past, and, in the case of testate amoebae, palaeoecological approaches may also be valuable.     

The Unabomber’s ethics

In this paper, I present and criticize Ted Kaczynski’s (“The Unabomber”) theory that industrialization has been terrible for humanity, and that we should use any means necessary, including violent means, to induce a return to pre‐industrial ways of living. Although Kaczynski’s manifesto, Industrial society and its future, has become widely known, his ideas have never before been subject to careful philosophical criticism. In this paper I show how Kaczynski’s arguments rely on a number of highly implausible philosophical premises. I further make the case that, although his theory as a whole should be rejected, Kaczynski raises a number of worries about technological development that ought to receive serious attention. Some of these worries have recently come to be shared by prominent defenders of human enhancement, including Nick Bostrom and Julian Savulescu. In the last section I indicate why I believe it is important that academic philosophers scrutinize ideas that motivate acts of violence.     

Which humans behave adaptively,and why does it matter?

There has long been debate about the relevance of evolutionary theory to the study of humans. To many of us, however, the debate has shifted from whether to proceed with an evolutionary approach to how to proceed. Increasingly, it has been argued that studies of the current reproductive function of human traits make little or no contribution to the understanding of the psyche (e.g., Symons 1989). Here, on the basis of arguments about the relationship between an adaptation and an adaptive outcome, and a review of studies that assess current adaptiveness, I argue to the contrary that knowledge of the contexts in which people do or do not behave adaptively provides important information about the nature of the mechanisms that comprise the human psyche. In particular, studies that indicate that people behave adaptively in at least some contemporary environments cast doubt on many nonevolutionary constructions of human nature, and can be used now to distinguish alternative evolutionary constructions that are at odds over many issues pentaining to the human psyche's ontogeny and evolutionary background, especially the extent to which the human psyche is general purpose.     

The Evolution of Language: A Comparative Review

For many years the evolution of language has been seen as a disreputable topic, mired in fanciful “just so stories” about language origins. However, in the last decade a new synthesis of modern linguistics, cognitive neuroscience and neo-Darwinian evolutionary theory has begun to make important contributions to our understanding of the biology and evolution of language. I review some of this recent progress, focusing on the value of the comparative method, which uses data from animal species to draw inferences about language evolution. Discussing speech first, I show how data concerning a wide variety of species, from monkeys to birds, can increase our understanding of the anatomical and neural mechanisms underlying human spoken language, and how bird and whale song provide insights into the ultimate evolutionary function of language. I discuss the “descended larynx” of humans, a peculiar adaptation for speech that has received much attention in the past, which despite earlier claims is not uniquely human. Then I will turn to the neural mechanisms underlying spoken language, pointing out the difficulties animals apparently experience in perceiving hierarchical structure in sounds, and stressing the importance of vocal imitation in the evolution of a spoken language. Turning to ultimate function, I suggest that communication among kin (especially between parents and offspring) played a crucial but neglected role in driving language evolution. Finally, I briefly discuss phylogeny, discussing hypotheses that offer plausible routes to human language from a non-linguistic chimp-like ancestor. I conclude that comparative data from living animals will be key to developing a richer, more interdisciplinary understanding of our most distinctively human trait: language.     

The isoprenoid substrate specificity of isoprenylcysteine carboxylmethyltransferase: development of novel inhibitors

Isoprenylcysteine carboxylmethyltransferase (Icmt) is an integral membrane protein localized to the endoplasmic reticulum of eukaryotic cells that catalyzes the post-translational alpha-carboxylmethylesterification of CAAX motif proteins, including the oncoprotein Ras. Prior to methylation, these protein substrates all contain an isoprenylcysteine residue at the C terminus. In this study, we developed a variety of substrates and inhibitors of Icmt that vary in the isoprene moiety in order to gain information about the nature of the lipophilic substrate binding site. These isoprenoid-modified analogs of the minimal Icmt substrate N-acetyl-S-farnesyl-L-cysteine (AFC) were synthesized from newly and previously prepared farnesol analogs. Using both yeast and human Icmt enzymes, these compounds were found to vary widely in their ability to act as substrates, supporting the isoprenoid moiety as a key substrate recognition element for Icmt. Compound 3 is a competitive inhibitor of overexpressed yeast Icmt (K(I) = 17.1 +/- 1.7 microm). Compound 4 shows a mix of competitive and uncompetitive inhibition for both the yeast and the human Icmt proteins (yeast K(IC) = 35.4 +/- 3.4 microm, K(IU) = 614.4 +/- 148 microm; human K(IC) = 119.3 +/- 18.1 microm, K(IU) = 377.2 +/- 42.5 microm). These data further suggest that differences in substrate specificity exist between the human and yeast enzymes. Biological studies suggest that inhibition of Icmt results in Ras mislocalization and loss of cellular transformation ability, making Icmt an attractive and novel anticancer target. Further elaboration of the lead compounds synthesized and assayed here may lead to clinically useful higher potency inhibitors.     

Mind, memory and history: How classifications are shaped by and through time, and some consequences

Understanding the history of systematics bears on contemporary issues such as the distinction between classifications and systems, the belief that ‘natural’ classifications reflect the progressive refinement of our ideas of relationships, and the dubious reputation acquired by systematics. Here I emphasize the extent to which ‘mind’ shapes classifications. I show that groups in biological classifications often have six or fewer members, in line with the number of things that humans can conveniently memorize together. Concerns about memorization are evident in the work of systematists like Tournefort, Linnaeus, and Antoine-Laurent de Jussieu, and the whole hierarchy of George Bentham's and J. D. Hooker's great Genera plantarum is structured by such concerns. An analytical element in Jussieu's work was emphasized by Cuvier and others, and the hierarchy of their classifications reflects more directly aspects of nature as they understood it, although concerns about memorisation remain evident. Linking an understanding of what classifications can represent to the ideas the makers of classifications had about nature makes it clear that classifications are rarely rigid class hierarchies, but are often more like systems. Historically, the synthetic approach, discussed here, tends to lead to systems, the analytical approach, to ‘classifications’. We must remember that systematists’ work is evaluated by other scientists, and by society at large. The confusion evident in systematics simply confirmed the negative perceptions that many people in the nineteenth century had of naturalists, botanists and zoologists, perceptions that persist today. Zoologica Scripta itself, and the Journal of Natural History, which under this title is about the same age, reflect part of this history. I conclude by emphasizing (1) if systems or classifications in the nineteenth century reflect ‘nature’, it is a nature very different from that we understand today, and (2) the extent and the persistence of the opposition between the synthetic and anaytical approaches.     

Identification of a Growth Factor produced by Human Fibroblasts <Emphasis Type="Italic">in vitro</Emphasis> as Putrescine

IT has been reported that medium modified by contact with living cells (conditioned medium) has a favourable effect on cell growth, but the nature of the effector has usually remained obscure. We report here the properties of a growth stimulating factor produced in cultures of human fibroblasts and show that most of its effect is due to putrescine (diaminobutane).     

Chemical machines, Maxwell's demon and living organisms

The problem considered in this paper is whether conventional chemical machines can be used in living organisms. I first point out that, due to their molecular nature, living systems pose unique thermodynamic problems, particularly in relation to Maxwell's demon. I then show that these problems may be solved by introducing time into the fundamental statement of the second law so that it becomes valid at the molecular level. This proposal, while clarifying certain logical anomalies in classical thermodynamics, makes no difference to that science in practice. However, I deduce from this statement that there are only two general ways of obtaining useful work from a chemical reaction: the first, a “constrained equilibrium” mechanism, is that employed by conventional chemical engines, but the second, a “molecular energy” mechanism, which depends upon the rapidity of resonant energy-transfer, may not have been suggested before. I then argue that because the former mechanism is essentially macroscopic in character it cannot, in fact, be used in those biological processes, like muscular contraction or active transport, in which useful molecular work is done and that only the latter may be so used. I also suggest reasons why this conclusion has been overlooked. Muscular contraction is used to illustrate these arguments and it is shown that all models of this process so far proposed fall into the first category. Although it is possible to eliminate such models a priori, several examples are finally criticized in detail to clarify the points raised. It is shown that in fact each of these models would have to be a Maxwell's demon machine.     

Normativity, agency, and life

There is an immense philosophical literature dealing with the notions of normativity and agency, as well as a sizeable and rapidly growing scientific literature on the topic of autonomous agents. However, there has been very little cross-fertilization between these two literatures. As a result, the philosophical literature tends to assume a somewhat outdated mechanistic image of living things, resulting in a quasi-dualistic picture in which only human beings, or the higher animals, can be normative agents properly speaking. From this perspective, the project of 'naturalizing normativity' becomes almost a contradiction in terms. At the same time, the scientific literature tends to misuse 'normativity,' 'agency,' and related terms, assuming that it is meaningful to ascribe these concepts to 'autonomous agents' conceived of as physical systems whose behavior is to be explained in terms of ordinary physical law. From this perspective, the true depth of the difficulty involved in understanding what makes living systems distinctive qua physical systems becomes occluded. In this essay, I begin the attempt to remedy this situation. After some preliminary discussion of terminology and situating of my project within the contemporary philosophical landscape, I make a distinction between two different aspects of the project of naturalizing normativity: (1) the 'Scope Problem,' which consists in saying how widely in nature our concept of normative agency may properly be applied; and (2) the 'Ground Problem,' which consists in rationalizing the phenomenon of normative agency in terms of the rest of our knowledge of nature. Then, in the remainder of this paper, I argue that the Scope Problem ought to be resolved in favor of attributing normative agency, in the proper sense of those words, to living things as such. The Ground Problem will be discussed in a companion paper at a later time.